全文获取类型
收费全文 | 3074篇 |
免费 | 332篇 |
国内免费 | 1篇 |
出版年
2023年 | 10篇 |
2022年 | 12篇 |
2021年 | 70篇 |
2020年 | 34篇 |
2019年 | 32篇 |
2018年 | 51篇 |
2017年 | 47篇 |
2016年 | 88篇 |
2015年 | 156篇 |
2014年 | 160篇 |
2013年 | 179篇 |
2012年 | 228篇 |
2011年 | 203篇 |
2010年 | 143篇 |
2009年 | 115篇 |
2008年 | 166篇 |
2007年 | 200篇 |
2006年 | 174篇 |
2005年 | 202篇 |
2004年 | 178篇 |
2003年 | 160篇 |
2002年 | 154篇 |
2001年 | 35篇 |
2000年 | 37篇 |
1999年 | 39篇 |
1998年 | 59篇 |
1997年 | 27篇 |
1996年 | 40篇 |
1995年 | 29篇 |
1994年 | 33篇 |
1993年 | 28篇 |
1992年 | 27篇 |
1991年 | 18篇 |
1990年 | 17篇 |
1989年 | 10篇 |
1988年 | 16篇 |
1987年 | 20篇 |
1986年 | 13篇 |
1985年 | 15篇 |
1984年 | 11篇 |
1983年 | 9篇 |
1982年 | 20篇 |
1981年 | 16篇 |
1979年 | 13篇 |
1978年 | 9篇 |
1977年 | 8篇 |
1976年 | 11篇 |
1975年 | 14篇 |
1971年 | 7篇 |
1968年 | 7篇 |
排序方式: 共有3407条查询结果,搜索用时 265 毫秒
971.
Sellge G Lorentz A Gebhardt T Levi-Schaffer F Bektas H Manns MP Schuppan D Bischoff SC 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(1):260-267
In rodents, fibroblasts (FBs) mediate stem cell factor (SCF)-dependent growth of mast cells (MCs). In humans, SCF is mandatory for MC differentiation and survival. Other factors such as IL-3, IL-4, and nerve growth factor (NGF) act in synergism with SCF, thus enhancing proliferation and/or preventing apoptosis in MCs. In this study, we studied in vitro interactions between human MCs and human FBs, both isolated from the intestine and purified to homogeneity. In coculture with FBs, MCs survived for up to 3 wk, whereas purified MCs cultured alone died within a few days. TNF-alpha and IL-1beta, which both did not affect MC survival directly, enhanced FB-dependent MC growth. We provide evidence that FB-derived MC growth factors are soluble, heat-sensitive molecules which down-regulate MC apoptosis without enhancing MC proliferation. However, only low amounts of SCF were measured in FB-conditioned medium (<0.2 ng/ml). Moreover, blocking of SCF/c-kit interaction by anti-SCF or anti-c-kit Abs and neutralization of IL-3, IL-4, and NGF did not affect MC survival in the coculture system. In conclusion, our data indicate that human FBs promote survival of human MCs by mechanisms independent of SCF, IL-3, IL-4, and NGF. Such interactions between MCs and FBs may explain why MCs accumulate at sites of inflammatory bowel disease and intestinal fibrosis. 相似文献
972.
Liu Y O'Connor MB Mandell KJ Zen K Ullrich A Bühring HJ Parkos CA 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(4):2578-2585
CD47, a cell surface transmembrane Ig superfamily member, is an extracellular ligand for signal regulatory protein (SIRPalpha). Interactions between CD47 and SIRPalpha regulate many important immune cell functions including neutrophil (PMN) transmigration. Here we report identification of a novel function-blocking peptide, CERVIGTGWVRC, that structurally mimics an epitope on CD47 and binds to SIRPalpha. The CERVIGTGWVRC sequence was identified by panning phage display libraries on the inhibitory CD47 mAb, C5D5. In vitro PMN migration assays demonstrated that peptide CERVIGTGWVRC specifically inhibited PMN migration across intestinal epithelial monolayers and matrix in a dose-dependent fashion. Further studies using recombinant proteins indicated that the peptide specifically blocks CD47 and SIRPalpha binding in a dose-dependent fashion. Protein binding assays using SIRPalpha domain-specific recombinant proteins demonstrated that this peptide directly bound to the distal-most Ig loop of SIRPalpha, the same loop where CD47 binds. In summary, these findings support the relevance of CD47-SIRPalpha interactions in regulation of PMN transmigration and provide structural data predicting the key residues involved on the surface of CD47. Such peptide reagents may be useful for studies on experimental models of inflammation and provide a template for the design of anti-inflammatory agents. 相似文献
973.
974.
The cis-requirements for the first editing site in the atp9 mRNA from pea mitochondria were investigated in an in vitro RNA editing system. Template RNAs deleted 5′ of −20 are edited correctly, but with decreased efficiency. Deletions between −20 and the edited nucleotide abolish editing activity. Substitution of the sequences 3′ of the editing site has little effect, which suggests that the major determinants reside upstream. Stepwise mutated RNA sequences were used as templates or competitors that divide the cis-elements into several distinct regions. In the template RNAs, mutation of the sequence between −40 and −35 reduces the editing activity, while the region from −15 to −5 is essential for the editing reaction. In competition experiments the upstream region can be titrated, while the essential sequence near the editing site is largely resistant to excess competitor. This observation suggests that either one trans-factor attaches to these separate cis-regions with different affinities or two distinct trans-factors bind to these sequences, and one of which is present in limited amounts, wheras the other one is more abundant in the lysate. 相似文献
975.
Lenoir M Djerdjouri B Périanin A 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(11):7136-7143
Classical chemoattractants such as fMLP or the complement factor C5a use G protein (Gi)-coupled receptors to stimulate both chemotaxis and production of reactive oxygen species (respiratory burst, RB) by polymorphonuclear leukocytes (PMN). The chemokine stroma cell-derived factor 1alpha (SDF1alpha) and its Gi-coupled receptor, CXCR4, regulate leukocyte trafficking and recruitment to the synovial fluid of rheumatoid arthritic patients (RA-SF). However, the role of SDF1alpha in the RB is unknown and was studied in this work in vitro with healthy PMN in the absence and presence of RA-SF. In healthy PMN, SDF1alpha failed to stimulate the RB, even though the p38 mitogen-activated protein kinase was activated to a similar level as in fMLP-stimulated PMN. In contrast, the SDF1alpha-mediated calcium transients and activation of phosphatidylinositol 3-kinase/Akt were partially deficient, while p44/42 mitogen-activated protein kinases were not activated. SDF1alpha actually desensitized weakly the fMLP-mediated RB of healthy PMN. This cross-inhibitory effect was amplified in PMN treated with RA-SF, providing a protection against the exacerbation of RB induced by C5a or fMLP. This SDF1alpha beneficial effect, which was prevented by the CXCR4 antagonist AMD3100, was associated with impairment of C5a- and fMLP-mediated early signaling events. Thus, although SDF1alpha promotes leukocyte emigration into rheumatoid synovium, our data suggest it cross-desensitizes the production of oxidant by primed PMN, a property that may be beneficial in the context of arthritis. 相似文献
976.
Large rigid-body domain movements are critical to GroEL-mediated protein folding, especially apical domain elevation and twist associated with the formation of a folding chamber upon binding ATP and co-chaperonin GroES. Here, we have modeled the anisotropic displacements of GroEL domains from various crystallized states, unliganded GroEL, ATPgammaS-bound, ADP-AlFx/GroES-bound, and ADP/GroES bound, using translation-libration-screw (TLS) analysis. Remarkably, the TLS results show that the inherent motions of unliganded GroEL, a polypeptide-accepting state, are biased along the transition pathway that leads to the folding-active state. In the ADP-AlFx/GroES-bound folding-active state the dynamic modes of the apical domains become reoriented and coupled to the motions of bound GroES. The ADP/GroES complex exhibits these same motions, but they are increased in magnitude, potentially reflecting the decreased stability of the complex after nucleotide hydrolysis. Our results have allowed the visualization of the anisotropic molecular motions that link the static conformations previously observed by X-ray crystallography. Application of the same analyses to other macromolecules where rigid body motions occur may give insight into the large scale dynamics critical for function and thus has the potential to extend our fundamental understanding of molecular machines. 相似文献
977.
978.
Lenoir M Muntaner O Pedruzzi E Roch-Arveiller M Tissot M Drieu K Périanin A 《Biochemical and biophysical research communications》2005,335(4):1149-1154
Ginkgolide B (GKB) is a bioactive component of the standardized extract from the leaves of the Ginkgo biloba tree (EGb 761), which is used in Chinese and in occidental medicine. GKB is known as a platelet-activating factor receptor antagonist. Here, we provide evidence that GKB per se (0.25-5 microM) stimulated tyrosine phosphorylation of proteins, phospholipase D activation, calcium transients, and activation of p38 but not p44/42 Map kinases in human polymorphonuclear leukocytes (PMN). These stimulatory effects remained relatively weak and primed PMN for subsequent stimulation of respiratory burst (RB) or directed locomotion by the chemoattractant fMet-Leu-Phe (fMLP) or complement-derived factor C5a. A similar RB priming was observed with rat exudate PMN after in vivo administration of EGb 761 (25 and 50 mg/kg) to rats before pleurisy induction. Thus, GKB primarily induces activation of intracellular signaling events and has the potential to prime cellular functions such as PMN defense activities. 相似文献
979.
Anti-inflammatory effects of phospholipid transfer protein (PLTP) deficiency in mice 总被引:2,自引:0,他引:2
Schlitt A Liu J Yan D Mondragon-Escorpizo M Norin AJ Jiang XC 《Biochimica et biophysica acta》2005,1733(2-3):187-191
We previously reported that phospholipid transfer protein-deficient (PLTP KO) mice exhibit a lower rate of atherosclerosis. We proposed two possible mechanisms: a reduction in hepatic apoB secretion (Nat Med 7 (2001) 847) and induction of lipoprotein anti-oxidation activity (J Biol Chem 277 (2002) 31850). We now hypothesized that PLTP KO mice may exhibit an anti-inflammatory state per se. First, we found that PLTP KO mice have significantly lower IL-6 levels than wild type (WT) mice. Secondly, we found that IL-6 treatment increased plasma TNFalpha levels in WT mice, but not in PLTP KO mice. Thirdly, we used flow cytometric analyses to measure the mean fluorescence intensity of I-A(b), a MHC-class II molecule, on peripheral monocytes and found that IL-6 treatment significantly increased the I-A(b)-positive cell levels in WT mice, whereas no changes were observed in the cell levels in PLTP KO mice. The results of our experiments demonstrated an anti-inflammatory effect of PLTP deficiency as a further aspect of its proatherogenic potency. 相似文献
980.
The unique C-terminal tail of the mitogen-activated protein kinase ERK5 regulates its activation and nuclear shuttling 总被引:4,自引:0,他引:4
ERK5 is unique among mitogen-activated protein kinases (MAPKs) in that it contains a large C-terminal tail. We addressed the question of how this tail could affect the signaling capacity of ERK5. Gradual deletion of the C-terminal domains resulted in a drastic increase of ERK5 kinase activity, which was dependent on the up-stream MAPK cascade, thus indicating a possible auto-inhibitory function of the tail. It is interesting that ERK5 was able to autophosphorylate its own tail. Moreover, ERK5, which was found to be expressed in virtually all kinds of cell lines, localized to nuclear as well as cytoplasmic compartments. The localization of ERK5 was determined by its C-terminal domains, which were also required for appropriate nucleocytoplasmic shuttling. Taken together, these results indicate that ERK5 signaling is directed by the presence of its unique C-terminal tail, which might be the key to understanding the key role of ERK5 in MAPK signaling. 相似文献